Contraception consists in the use of different methods to prevent fecundation or pregnancy when having sexual intercourse. Currently, there are different methods to avoid fecundation, which can be classified into barrier methods and chemical or hormonal methods.
Spermicides, which are chemical compounds that kill or inactivate spermatozoa, are one of the most prominent members of the chemical methods.
Spermicides, from a physiological point of view, must affect spermatozoid motility or by affecting the capacitive response, altering the membrane potential by blocking specific currents of any ionic species relevant to complete sperm maturation (such as calcium), blocking progesterone receptors or receptors of substances that act as chemotactic components for the spermatozoid.
One of the spermicides that have been used in some countries is Nonoxynol-9, a bioorganic molecule that exerts its action mainly as a biodetergent for membrane structures. It causes a partial digestion of the lipids that form the membrane barrier. In this way, the biodetergent cause micropores to form on the membrane, destroying the barrier that separates the intracellular and extracellular spaces, which finally establishes a transmembrane thermodynamic equilibrium that causes cell death. The pharmaceutical forms of Nonoxynol-9 comprise being used as an additive to barrier contraceptive methods (condom), as part of a lubricant and spermicide; vaginal ovules containing 168 mg of the substance; contraceptive sponges with 1,000 mg of the substance; lubricant gels for vaginal use and vaginal diaphragms. The side effects of this molecule have made the Food and Drug Administration (FDA) of the United States of America to reject the approval for use. These undesired effects are produced because Nonoxynol-9 causes clinical settings of irritation, inflammation and keratosis in other cellular tissues (vaginal mucose, cervix and lining membranes of labium majus and labium minor in women, and surface of the lining epithelium of the glans and the lining epithelium of the urinary meatus in men). Hence, when the molecule is applied to the genital zone of one or both members of the couple, the probability of infection with a Sexually Transmitted Disease (STD) is increased, as some WHO reports have linked the repeated use of Nonoxynol-9 with urinary tract infections. For example, lubricant gels have been designed to be used intravaginally. However, some people use these gels intrarectally, which could promote disruption of the rectal epithelium due to the presence of Nonoxynol-9. (Phillips D M et al. 2000)
Spermicides can be natural of synthetic. A natural spermicide example is gossypol. Since 1950, gossypol was extracted in China from cottonseeds. This product is a potent male contraceptive since it inhibits competitively the lactic dehydrogenase enzyme, which is important in sperm cell production. It was used at concentrations from 75 to 100 μg twice a month. The problem associated with this molecular structure was that it caused chemical sterilization in the subjects, and therefore it could not be patented as a chemical spermicide, and it further caused hypokalemia, effects in the digestive system, fatigue and paralysis in extreme cases.
The work of Reddy et al., “Antimicrobial peptides: premises and promises” International Journal of Antimicrobial Agents 24 (2004) 536-547, describes the potential use of antimicrobial peptides as contraceptives that alter the ion flux through spermatozoid membranes. This work mentions magainin-A and nisin as examples of such peptides. However, no reference was made about natural or synthetic analog peptides obtained from a fraction of the Latrodectus mirabilis venom.
Yeung et al., in “Effects of the ion-channel blocker quinine on human sperm volume, kinematics and mucus penetration, and the involvement of potassium channels” Molecular Human Reproduction Vo1.7, No. 9 pp. 819-828, 2001, describe the effects of quinine on different ionic channels, particularly the consequences on cellular volume. They mention that said channels could be the targets of potential contraceptives, but no application examples are presented and no suggestions about other peptides with a similar action are made. Particularly, extracts from the Latrodectus mirabilis venom are not mentioned.
The patent application EP448464A1 describes a method to determine if a spermatozoid suffers the acrosomal reaction, using proteins C3, C3b or iC3, or fragments thereof. This document describes that antibodies against said proteins or protein fragments could be used as male or female contraceptive vaccines. Even though this document mentions peptide or protein alternatives, its objective is the creation of a contraceptive vaccine, which differs from the present invention, which is related to a spermicide based on extracts from the Latrodectus mirabilis venom or a synthetic peptide based on the nucleotide sequences obtained from said extract.
The U.S. Pat. No. 6,897,291B1 describe ionic channels that can be used to identify molecules that could potentially be used as contraceptives, however this document does not describe new contraceptive or spermicide molecules, but only a method to identify said molecules.
The Australian Patent AU772403B2 describe polypeptides based on FSP95, a protein that is located in the spermatozoid tail and has a function in sperm motility once the spermatozoid has been capacitated. The use of said polypeptides with contraceptive methods is mentioned, however, no information regarding their effectiveness is provided in said publication, since no biological data are described.
The US Patent Applications US20040157292-A1, US20090104604-A1, US20060257868-A1, US20090249499-A1, describe different ionic channels (CatSper1, CatSper2, CatSper3, CatSper4, respectively). Said channels are used to diagnose infertility, and all documents mention the use of preparations containing inhibitors of said channels as possible contraceptives. Particularly, antibodies against said ionic channels are mentioned, but no contraceptive peptides are suggested or mentioned.
The US Patent Application US20070105188A1 describes methods to identify potential contraceptive molecules, but do not describe such molecules.
In conclusion, there is no peptide, organic or immunological inhibitor molecule in the current state of the art that presents spermicidal properties and that could be used to prepare a viable pharmaceutical product to inhibit spermatozoa.